The neurotransmitter serotonin (5-hydroxytryptamine or “5-HT”) is the subject of intensive research; anomalies in the processing of serotonin are a component of various disease profiles. Serotonin acts in the cardiovascular, gastrointestinal, and central nervous systems by binding to various types of 5-HT receptors. At least seven different receptor classes mediate the physiological activities of serotonin. These receptor classes are designated as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 according to an internationally recognized classification system. Most of these classes include further distinguishable receptor subtypes; thus, the 5-HT1 class includes receptors which in turn may be divided into at least five subclasses, designated 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT1E (Boess, Martin; Neuropharmacology 33: 275-317 (1994)).
The properties, function, and pharmacology of these receptor subtypes have been summarized, for example, by: (a) Kennet G. A., “Serotonin Receptors and Their Function,” TOCRIS Review (http://www.tocris.com/serotonin.htm), published May 1997; and (b) Peroutka, S. J., 1994, “Molecular Biology of Serotonin (5-HT) Receptors,” Synapse 18, 241-260 and Current Drug Targets—CNS & Neurological Disorders 2004, 3, Issue 1.
The 5-HT5 class was first described by Plassat et al., The EMBO Journal, Vol. 11, No. 13, pp. 4779-4786 (1992). A distinction is made between 5-HT5A and 5-HT5B receptors (Erlander et al., Proc. Natl. Acad. Sci. USA 90:3452-3456 (1993). 5-HT5 receptors belong to the family of G protein-coupled receptors, and are negatively coupled to adenylyl cyclase. 5-HT5 receptors have been cloned using mouse, guinea pig, rat, and human cDNA. Despite a high interspecies homology, there are only slight sequence homologies between 5-HT5 receptors and other 5-HT receptors.
5-HT5 receptors may be localized in the hippocampus, cerebellum, hypothalamus, thalamus, and striatum, cortex, for example, using molecular biological techniques. Immunohistochemical methods have shown that 5-HT5 receptors of neurons are expressed in various regions of the brain (Oliver et al., Brain Res. 2000, 867, 131-142; Pasqualetti et al., Mol. Brain. Res. 1998, 56, 1-8). On the one hand these 5-HT5 receptors may directly or indirectly modulate important functions of the brain, and on the other hand may also participate in mechanisms involved in neuropathological, neurodegenerative, and neuropsychiatric diseases. 5-HT5 receptors have also been localized in astrocytes (Carson et al., GLIA 17:317-326 (1996)). Reactive astrocytes have been observed in conjunction with reactive gliosis for a number of pathological brain changes and neuropsychiatric diseases. In vitro tests of cultivated astrocytes have shown 5-HT5 receptor-mediated responses. For this reason it is suspected, on the one hand, that 5-HT5 receptors are involved in healing processes of the brain subsequent to disorders, but on the other hand it cannot be ruled out that they also contribute to the origin or even proliferation of damage.
5-HT5 receptors show a high affinity for various antidepressants and antipsychotic agents. Previous studies indicate that 5-HT5 receptors play a role in the following disease profiles:
Psychosis, depression, chronic schizophrenia, other psychotic conditions, anxiety, bipolar disorders, dementia, in particular Alzheimer's dementia, demyelinating diseases, in particular multiple sclerosis, and ischemia, stroke, and migraines.
The use of 5-HT5 receptor ligands for the general treatment of migraines and other cerebrovascular diseases is described in WO 00/041472, and for the treatment of neurodegenerative and neuropsychiatric diseases, in WO 00/041696.
Imidazole compounds have not been used heretofore as 5-HT5 ligands.
Substituted imidazoles, triazoles, and pyrazoles are known, for example, as kinase inhibitors, as inhibitors of various phosphodiesterase subtypes, as angiotensin receptor antagonists, and as polymerase inhibitors.
WO 2005028448 describes benzyl-substituted benzimidazoles as tyrosine kinase inhibitors. EP 545845 (U.S. Pat. No. 5,314,903) describes the preparation and use of substituted N-alkylphenylaminobenzimidazoles as calcium channel blockers. WO 9724334 (U.S. Pat. No. 6,352,985, U.S. Pat. No. 6,166,219, EP 882718) describes “carbonyl”-substituted N-alkylphenylalkylaminobenzimidazoles and their use as PDE5 inhibitors. EP 111993 describes the preparation of “carbonyl”-substituted N-alkylaminobenzimidazoles and their use as antiviral compounds. WO 9855120 describes benzoyl-substituted N-alkylaminobenzimidazoles and their use as antiviral compounds, and WO 9962908 describes, among other things, benzimidazole derivatives and their use as cell adhesion inhibitors. WO 200272549 and WO 200276960 relate to functionalized indoles and benzimidazoles and their use as kinase inhibitors. Lastly, benzoyl-substituted benzimidazoles are described in Russian Journal of General Chemistry 2004, 74 (5), 738-743. WO 200288094 describes the preparation of N,N′-disubstituted iminobenzimidazoles and their use as thrombin inhibitors, and WO 200253158 describes, among other things, the preparation and use of N,N′-disubstituted imidazolium compounds for the treatment of glaucoma.
WO 2001081326 describes 5-ring heteroaromatic compounds having phenethyl side chains as modulators of the α4β21 receptor. WO 2001098276 and WO 2000031067 relate to the use of imidazoles as hair colorants, and pyridyl-substituted imidazoles are described in U.S. Pat. No. 6,303,638. WO 9215577 describes imidazole toluoyl pyrroles as angiotensin receptor antagonists. Imidazolones as platelet aggregation inhibitors are described in Journal of Medicinal Chemistry 1982, 17 (6), 547-556. Imidazoles as intermediate products are described in WO 9736875. The activity and synthesis of imidazoles in natural substances are described in Heterocycles 2003, 60 (3), 583-598, Journal of Natural Products 2002, 65 (8), 1190-1193 and 1991, 54 (6), 1509-1515, Journal of Organic Chemistry 1999, 64 (7), 2540-2544, and Tetrahedron 1989, 45 (7), 2193-2200. 1 Translator's note: Assumed for “□4□2” in the source.
Benzyl-substituted aminotriazoles for the treatment of autoimmune diseases are described in JP 2002275165, and the use of phenyl-substituted triazoles as insecticides and glycine transporters is described in JP 02091062, EP 285893, and WO 2001087855.
Synthesis examples for phenyl-substituted triazoles are found in Compte Rendues des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques 1978, 287 (4), 121-123, Synthesis 1979, (5), 359-361, and Chemistry & Industry, 1978, (3), 92-94, WO 2002004424 describes pyrazoles and their use in the treatment of HIV infections.